Bupivacaine Liposome Injectable Suspension Monograph

Bupivacaine Liposome Injectable Suspension

(EXPAREL)

National Drug Monograph

June 2013

VA Pharmacy Benefits Management Services,

Medical Advisory Panel and VISN Pharmacist Executives

The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current.

Executive Summary

Description

  • Bupivacaine liposomal injectable suspension (Exparel) is an amide-type local anestheticin an encapsulated liposomal formulation developed with the goal of providing a longer duration of anesthesia compared with its non-liposomal counterpart, bupivacaine hydrochloride or other local anesthetics.
  • The product utilizes the DepoFoam drug delivery system consisting of an aqueous suspension of multivesicular liposomes containing bupivacaine in a honeycomb-like structure that allows for a more gradual release.
  • The FDA approved bupivacaine liposomal in October 2011 for single-dose infiltration into the surgical site for postoperative analgesia.

Efficacy

  • To date, there have been a limited number of published clinical trials evaluating the safety and efficacy of liposomal bupivacaine.
  • Three phase 3 pivotal trials were reviewed by the FDA for final approval, two of them comparing liposomal bupivacaine to placebo and one comparing liposomal bupivacaine to unencapsulated bupivacaine HCl/epinephrine (unpublished). In each of the trials, the primary endpoint was pain intensity and duration using the numeric pain rating score through a predetermined period of time postoperatively (24, 72 and 96 hrs). In the placebo-controlled trials (1-bunionectomy4, 1-hemorrhoidectomy5), liposomal bupivacaine was associated with statistically less intense pain through the stated time period compared to placebo. In addition, opioid consumption was statistically less in favor of liposomal bupivacaine versus placebo, but the clinical significance of the difference is unknown (Golf-3.8 vs. 4.7 tabs of oxycodone 5 mg/APAP 325 mg tablets at 24 hrs, p=0.008 and Gorfine-22.3 mg vs. 29.1 mg morphine equivalents at 72 hrs, p=0.0006). In an unpublished study, liposomal bupivacaine was not statistically different from unencapsulated bupivacaine HCl/epinephrine in reducing pain intensity through the specified time points or other secondary outcome measures in patients following hemorrhoidectomy.
  • The FDA reviewer highlighted some important points regarding the results of these three trials as follows:
  • In the two pivotal, placebo controlled trials,liposomal bupivacaine provided postoperative analgesia for up to 24 hours in patients having bunionectormy or hemorrhoidectomy surgery. In these studies, pain intensity was significantly reduced in patients receiving liposomal bupivacaine compared to placebo for the initial 12 hours after infiltration, but diminished over the subsequent 12 hours resulting in no clinical meaningful difference in pain between groups beyond 24 hrs.
  • Unpublished, active comparison: Based upon the results, investigators failed to show any statistically or clinically meaningful advantage of liposomal bupivacaine over bupivacaine HCl when used after hemorrhoidectomy, despite examining over 60 different efficacy endpoints. Both agents were equally well tolerated.
  • The manufacturer did request a priority review. However, that request was denied since the manufacturer was unable to demonstrate that use of liposomal bupivacaine reduced the use of opioids or their associated adverse events or a relevant benefit in reduced time to discharge or return to usual activities.
  • Since different doses and manner of administration were used in the two types of surgery, extrapolation of dosing and effectiveness to other surgical interventions is not possible. Additional studies are needed to answer the question of appropriate dose and manner of administration for use in other surgeries.
  • Original recommendation was for the labeling to specifically include postoperative use following bunionectomy or hemorrhoidectomy. The final labeling was less specific.
  • Labeling should contain a strong caution against use of liposomal bupivacaine by other administration routes (other than single-dose, postoperative wound infiltration) that are commonly used with other local anesthetics in clinical practice but may be unsafe for this product.
  • There have been two published phase 2 trials (1-hemorrhoidectomy9, 1-total knee arthroplasty10) and two published phase 3 trials (1-total knee arthroplasty11, 1-breast augmentation18) comparing the cumulative pain scores between liposomal bupivacaine and unencapsulated bupivacaine HCl (0.25% with epinephrine 1:200,000).
  • In the phase-2 studies, the primary endpoint of cumulative pain intensity was met in favor of the liposomal product9,10 but not in the phase-3 studies11,18. However, since the analysis of pain intensity was determined over the entire planned study length (through 72 hrs or 4 days), the differences at the various time points were not entirely consistent between studies making it difficult to determine the actual length of time the differences between groups existed or if the differences were clinically important. For example in the pivotal trials, the primary endpoint was reportedly met through 72 hrs but when the FDA reviewer reported their findings, the statistical difference from placebo was present only through 24 hours, but not beyond.
  • In each of the studies, sample sizes were small, multiple comparisons between groups at a number of time points were made with some showing statistical benefit of the liposomal product and others not, and post-hoc changes were made to the analysis of one of the studies, thereby limiting the strength of the evidence.9
  • In three of the studies9,10,11, there was no statistical or clinically important difference in total consumption of opioids, discharge readiness, proportion of patients who were opioid free or who were able to return to work or resume normal daily activities between groups.

Safety

  • Liposomal bupivacaine was well tolerated and adverse events were not significantly different than bupivacaine HCl/epinephrine or placebo when administered as a single-dose infiltrated into the surgical site after bunionectomy or hemorrhoidectomy.
  • The most common adverse events reported with bupivacaine liposomal injectable suspension were constipation, nausea, and vomiting.
  • Similar to other local anesthetics, there is a potential for neurologic or cardiovascular adverse events and is related to the total dose administered. However, other factors may increase the incidence of these adverse events and include the specific anesthetic used, the route of administration and the patient’s health status. Early signs of central nervous system toxicity include restlessness, anxiety, incoherent speech, lightheadedness, numbness, tingling of the mouth and lips, metallic taste, tinnitus, dizziness, blurred vision, twitching, tremors, depression, or drowsiness.
  • There are no known long-term safety issues that have been identified to date.
  • Since liposomal bupivacaine has not been studied or data are limited in patients undergoing other types of surgery (other than bunionectomy or hemorrhoidectomy), the safety, efficacy and appropriate doses of liposomal bupivacaine are not known and therefore, use is not recommended.
  • Furthermore, other routes of administration or types of analgesia have not been studied and therefore, are not recommended (e.g., epidural, intrathecal, regional nerve block or intravascular or intra-articular use).

Conclusion

  • Although liposomal bupivacaine statistically reduced pain intensity in patients undergoing bunionectomy or hemorrhoidectomy when compared to placebo, there was no difference in the primary outcome or secondary outcomes when compared to traditional unencapsulatedbupivacaine HCl in an unpublished phase 3 pivotal trial in patients undergoing hemorrhoidectomy.
  • In two phase 2, dose-ranging studies, liposomal bupivacaine was associated with improved cumulative pain scores compared to bupivacaine HCl but differences in total consumption of opioids, readiness for discharge, proportion of patients who were opioid free or who were able to return to work or resume normal activities were not different.
  • Since the safety and efficacy of liposomal bupivacaine has been evaluated primarily in patients undergoing hemorrhoidectomy or bunionectomy (using a single-dose infiltrated into the surgical site), the safety and efficacy when used after other surgeries; by other routes of administration; or use for other types of analgesia are unknown and therefore, use after other surgeries is not recommended.
  • Based on the existing evidence, there are no clear or substantive advantages of the liposomal bupivacaine product over bupivacaine HCl.
  • There are no clinical trials comparing liposomal bupivacaine to other local anesthetic agents so any advantage or disadvantage of liposomal bupivacaine over other local anesthetics is unknown.

Introduction

The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating bupivacaine liposome injectable suspension for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA.

Pharmacology/Pharmacokinetics1,2

Bupivacaine liposomal injectable suspension is an amide-type local anesthetic in an encapsulated liposomal formulation developed to provide a longer duration of anesthesia compared with its non-liposomal counterpart, bupivacaine hydrochloride or other local anesthetics. Anesthesia occurs by reversibly binding to sodium channels on the neuronal cell wall, preventing the influx of sodium, and increasing the nerve’s electrical excitation threshold. Action potential firing is reduced and the nerve’s impulse generation and conduction are blocked. Small unmyelinated C-fibers are blocked first, which mediate pain, followed by small myelinatedAδ-fibers which mediate pain and temperature sensation, and lastly large myelinated fibers including Aγ-, Aβ-, and Aα- fibers which mediate touch, pressure, muscle and postural sensations.

Bupivacaine liposomal injectable suspension utilizes the DepoFoam drug delivery system, an aqueous suspension of multivesicular liposomes containing bupivacaine, for gradual systemic release. Themultivesicular liposome particles are made up of a honeycomb like structure consisting of many nonconcentric compartments containing bupivacaine. In vivo, DepoFoam particles release drug over an extended period of time by erosion of the exterior surface and reorganization of the particles’ lipid membranes. Bupivacaine liposomal injectable suspension follows a two-compartment model. Initially, first order short-term release followed by zero-order release over an extended period of time. When bupivacaine liposomal injectable suspension is administered, free bupivacaine in the solution is immediately available to anesthetize the surgical site, while the bupivacaine enclosed in the DepoFoam is released more gradually over an extended period of time.

Once Bupivacaine liposomal injectable suspension is released from the liposome, distribution, metabolism, and excretion follows the same kinetics as bupivacaine HCl. Of note, bupivacaine liposomal injectable suspension can have elevated systemic plasma levels for up to 96 hours, but the systemic plasma levels do not correlate with local efficacy. Duration of local analgesia properties is ~24 hours. Different formulations of bupivacaine are not bioequivalent and it is not possible to convert dosing from one formulation to another.1

Table 1. PK Parameters of Bupivacaine Liposomal Injectable Suspension1

Parameters / Bunionectomy 106 mg (8 mL)
(N=26) / Hemorrhoidectomy 266 mg (20 mL)
(N=25)
Mean Cmax (ng/mL) / 166(92.7) / 867 (353)
Median Tmax (h) / 2 / 0.5
Mean AUC(0-t) (h*ng/mL) / 5864 (2038) / 16,867 (7868)
Mean AUC (inf) (h*ng/mL) / 7105 (2283) / 18,289 (7569)
Mean t 1/2 (h) / 34.1 (17.0) / 23.8 (39.4)

Table adapted from product information

Table 2. PK parameters of bupivacaine liposomal injectable suspension and bupivacaine HCl2,3

PK Parameter / EXPAREL / Bupivacaine HCl
Metabolism / Hepatic conjugation with glucuronic acid; inactive metabolite pipecoloxylidine (PPX) / Hepatic conjugation with glucuronic acid; inactive metabolite pipecoloxylidine (PPX)
Elimination / Urine (6% unchanged) / Urine (6% unchanged)
Half-life / 24-34 h / 2.7 h
Protein binding / 95% / 95%
Local onset / 2 minutes / 1-17 minutes
Duration / Local: 24 h
Systemic: 96 h (does not correlate with local efficacy) / 2-9 h (route and dose dependent)
Time to peak / Bunionectomy: 2 h
Hemorrhoidectomy: 0.5 h
Inguinal hernia: 12 h
Total Knee Arthroplasty: 36 h / 0.5 hours-0.75 h

Bupivacaine liposomal injectable suspension is not associated with major motor blockade at doses up to 266 mg. When motor block did occur, the maximum duration was 4 hours instead of 12 hours as seen with unencapsulated bupivacaine.17

FDA Approved Indication(s)1

Bupivacaine liposomal injectable suspension is indicated for single-dose infiltration into the surgical site to produce anesthesia after surgery. The U.S. Food and Drug Administration approved it on October 28, 2011. Of note, the pivotal trials providing the basis for FDA approval consisted of patients having bunionectomy or hemorroidectomy.

Potential Off-label Uses

This section is not intended to promote any off-label uses. Off-label use should be evidence- based. See VA PBM-MAP and Center for Medication Safety’s Guidance on “Off-label” Prescribing (available on the VA PBM Intranet site only).

Bupivacaine liposomal injectable suspension has been studied for use in postoperative local analgesia in adults having hernia repair, breast augmentation, and total knee arthroplasty. There are also several phase 4 trials currently recruiting patients. Investigators for these trials will examine bupivacaine liposomal injectable suspension in comparison to morphine or other opioids for pain associated with colectomy, ileostomy reversal and robotic assisted laparoscopic prostatectomy.20-22Most of these trials are designed as health-economic trials. There is one planned trial to examine femoral nerve block with liposomal bupivacaine in patients having total knee arthroplasty. At this time, evidence is lacking to support the efficacy and safety of liposomal bupivacaine for post-operative local anesthesia in surgeries other than bunionectomy or hemorroidectomy, and therefore use in other surgeries cannot be recommended. Furthermore, evidence is lacking for use of other types of analgesia or routes of administration for liposomal bupivacaine (e.g., epidural, intrathecal, regional nerve blocks, etc.) and therefore should not be used outside of its approved dosage and administration.

Current VA National Formulary Alternatives

Current VA National Formulary Injectable local anesthetics (VA Class CN204) include: bupivacaine HCl*, chloroprocaine HCL, prilocaine, lidocaineHCl, mepivacaineHCl, ropivacaineHCl, and tetracaineHCl. Lidocaine, bupivacaine and prilocaine combined with epinephrine are also on the VANF.

*It is important to note that when using non-liposomal bupivacaine, there are multiple formulations with and without preservative. Bupivacaine multi-dose vials with methylparaben as a preservative can only be used for peripheral nerve block. The preservative free versions (also referred to as methylparaben free) are required for caudal or epidural anesthesia. For spinal anesthesia, bupivacaine spinal, which also contains dextrose, is the only bupivacaine product indicated.

Dosage and Administration1

Bunionectomy (Adult): Inject 106 mg by infiltrating 7 mL into surrounding tissue of the osteotomy and 1 mL into the subcutaneous tissue. Bupivacaine liposomal is intended for single-dose infiltration only and the maximum dose should not exceed 266 mg. The recommended dose is based on surgical site and volume needed to cover the surgical area.

Hemorrhoidectomy (Adult): Dilute 20 mL vial of bupivacaine liposome with 10 mL of normal saline for a total of 30 mL. Inject 266 mg via infiltration by dividing the 30 mL mixture into six 5-mL aliquots. Visualize the anal sphincter as a clock face and perform anal block by slowly infiltrating one aliquot to each of the even numbers. Liposomal bupivacaine is intended for single-dose infiltration only and maximum dose should not exceed 266 mg.

Safety and efficacy of bupivacaine liposome have not been established in patients less than 18 years of age. Bupivacaine liposomal injectable suspension should be used with caution in patients with hepatic and renal impairment (Refer to section on Special Populations for additional information).

Administration: Bupivacaine liposomal injectable suspension is indicated for single-dose infiltration only.

  • A 25-gauge or larger bore needle should be used to administer bupivacaine liposomal. Do not filter or heat before use. Invert vials several times to re-suspend particles immediately before withdrawing drug from vial.
  • Do not administer if vial has been frozen (as reflected by the temperature indicator) or exposed to high temperatures (40C or 104F) for an extended period of time. Freeze indicator turns from green to white if product has been exposed to freezing temperatures.
  • Inspect product for discoloration, do not administer if product is discolored.
  • Bupivacaine liposomal should be injected into the surrounding soft tissue of the surgical site. Frequent aspiration should be done to check for blood and to reduce the risk of intravascular administration. The maximum dose is 266 mg and should not be exceeded.
  • Bupivacaine liposomal can be administered diluted up to 0.89 mg/ml (i.e., 1:14 dilution by volume) with preservative free normal sterile saline (0.9%) for injection or undiluted.
  • Non-bupivacaine based local anesthetics may cause immediate release of bupivacaine from bupivacaine liposomal injectable suspension if administered together locally. Administration of bupivacaine liposomal injectable suspension may follow the administration of lidocaine after at least 20 minutes. Other formulations of bupivacaine should not be used within 96 hours due to risk of toxicity.
  • When a topical antiseptic (povidone iodine) is applied to site, the site should be allowed to dry before liposomal bupivacaine is administered since topical antiseptics should not come into contact with liposomal bupivacaine.

Storage: Store refrigerated between 2°C to 8°C. Unopened vials may be kept at room temperature (20 to 25°C) for up to 30 days. Record the date when a vial is removed from refrigeration.Unopened vials should not be re-refrigerated. After withdrawal from vial, the suspension may be stored up to 4 hours at room temperature. Diluted suspensions should be used within 4 hours.

Dose conversion: Bupivacaine liposomal injectable suspension is not bioequivalent with other formulations of bupivacaine, even if the milligram strength is the same. Therefore, dosage conversion between bupivacaine liposomal and other forms of bupivacaine, and vice versa, is notpossible.

Efficacy

For this review, all published studies examining the efficacy and/or safety of bupivacaine liposomal injectable suspension for producing post-surgical, local anesthesia in humans were included.

Efficacy Measures

Primary Outcome Measure:

  • Pain Intensity-Assessed by the cumulative pain score using the numeric rating scale (NRS) area under the curve (AUC) through a designated period of time (e.g., 0-24 hrs, 0-72 hrs, etc.). At designated time points, patients rate their pain intensity at rest or with activity on an 11-point scale (0=no pain, 10=worst pain possible). The pain assessment ratings are then summed during the time points and the NRS-AUC for the period of time is obtained.

Secondary Outcome Measures: